During osteogenesis, mesenchymal stem cells are recruited to the osteoblast lineage and progressively differentiate into osteoblasts that produce a mineralised extracellular matrix. Although most of the organic component of this matrix is comprised of collagen, growing evidence suggests the most bioactive element of a developing matrix is its heparan sulfate glycosaminoglycan complement. This species of linear, unbranched sugars contain protein-binding domains that regulate the flow of an astonishing number of mitogenic influences that coordinate mesenchymal stem cell commitment and growth, and ultimately, osteoblast phenotype. Among the heparan sulfate-binding factors known to be important to this process are sonic hedgehog, the fibroblast growth factors and their receptors, members of the transforming growth factor superfamily, as well as the collagens, laminins and fibronectins. How these sugars change during development to bring together the right combination of mitogenic/differentiative influences to trigger the successive phases of osteogenesis is currently the focus of intense research.